Antiviral Compounds

ABSTRACT

The present invention provides compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

FIELD OF THE INVENTION

The present invention provides compounds of Formula I and certainderivatives thereof, which are useful as inhibitors of hepatitis C virus(HCV) replication, and for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is a major health problem that leadsto chronic liver disease, such as cirrhosis and hepatocellularcarcinoma, in a substantial number of infected individuals. Currentstandard treatments for HCV infection is a combination of pegylatedinterferon-α (PEG-IFNα) with ribavirin (RBV) that leading to a sustainedviral response (SVR) in ˜80% in patients infected with HCV genotypes 2and 3, and between 40-50% in those with genotype 1 (Ghany M G et al.2009. Hepatology 49(4): 1335-1374). Systemic administration of IFN isassociated with numerous side effects, and significant efforts arecurrently being pursued to develop IFNα-free therapy, mostly by directlytargeting HCV proteins involved in viral replication (direct-actingantivirals, DAAs). While DAAs such as NS3 protease and NS5A inhibitorshave been shown to increase SVR when given with PEG-IFNα, these classesof compounds induced rapid selection of resistant virus in vivo (SorianoV et al. 2011. Antimicrob. Chemother. 66: 1673-1686). Thus, otheralternatives for HCV treatment are to develop drugs that has higherbarrier to resistance such as nucleos(t)ide analog of viral NS5Bpolymerase, or those target host factor(s) required for virusreplication, or combination of both. Host factors are well conserved andtherefore, drugs interfering with such factors are expected to be activeacross different genotypes and less likely to induce development ofresistant virus (Buhler S & Bartenschlager R. 2012. Liver Int. doi:10.1111/j.1478-3231).

The development and success of DAA is attributed to the robust cellculture system that supports self-replicating HCV RNA. This system,so-called replicon, contains part of HCV genome that is required forviral replication. The replicon system provided the first functionalcell-based platform for screening of antiviral agents targeting HCV RNAreplication and for validation of compounds directed against recombinantviral enzymes such as NS3 protease. Likewise, replicon system can beused to discover novel compounds that act on host targets required forHCV replication.

There is a clear and long-felt need to develop effective therapeuticsfor treatment of HCV infection. Specifically, there is a need to developcompounds that are useful for treating HCV-infected patients andcompounds that selectively inhibit HCV viral replication.

SUMMARY OF THE INVENTION

The application provides a compound of Formula I

wherein:

-   n is 1 or 2;-   Q is phenyl or naphthalene substituted with one or more Q′;

Q′ is hydroxyl, lower alkyl, or halo;

-   R¹ is lower alkyl, cycloalkyl, phenyl, or heterocycloalkyl;-   R² is —C(═O)OR² , —C(═O)R^(2′), —C(═O)ON(R^(2′))₂, monocyclic or    bicyclic heteroaryl, optionally substituted with one or more R^(2′);

each R^(2′) is independently H, lower alkyl or heterocycloalkyl;

-   R³ is H or lower alkyl; and-   X is CH₂ or C(═O);-   or a pharmaceutically acceptable salt thereof.

The application provides a method for treating a Hepatitis C Virus (HCV)infection comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula I.

The application provides a composition comprising a compound of Formulaand a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

As used herein, unless specifically indicated otherwise, the word “or”is used in the “inclusive” sense of “and/or” and not the “exclusive”sense of “either/or”.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formuladepicting and describing compounds employed or claimed in the presentinvention, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such compounds result in stablecompounds.

The symbols “*” at the end of a bond or “- - - ” drawn through a bondeach refer to the point of attachment of a functional group or otherchemical moiety to the rest of the molecule of which it is a part. Thus,for example:

MeC(═O)OR⁴ wherein

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen atom or a substituent.

The phrase “optional bond” means that the bond may or may not bepresent, and that the description includes single, double, or triplebonds. If a substituent is designated to be a “bond” or “absent”, theatoms linked to the substituents are then directly connected.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

Certain compounds may exhibit tautomerism. Tautomeric compounds canexist as two or more interconvertable species. Prototropic tautomersresult from the migration of a covalently bonded hydrogen atom betweentwo atoms. Tautomers generally exist in equilibrium and attempts toisolate an individual tautomers usually produce a mixture whose chemicaland physical properties are consistent with a mixture of compounds. Theposition of the equilibrium is dependent on chemical features within themolecule. For example, in many aliphatic aldehydes and ketones, such asacetaldehyde, the keto form predominates while; in phenols, the enolform predominates. Common prototropic tautomers include keto/enol—C(═O)—CH-□-C—(—OH)═CH—), amide/imidic acid (—C(═O)—NH-□-C(—OH)═N—) andamidine (—C(═NR)—NH-□-C(—NHR)═N—) tautomers. The latter two areparticularly common in heteroaryl and heterocyclic rings and the presentinvention encompasses all tautomeric forms of the compounds.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl,”“haloalkyiheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl,” or “hydroxyalkyl,” this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (het)aryl refers to either an aryl or a heteroarylgroup.

The term “spirocycloalkyl”, as used herein, means a spirocycliccycloalkyl group, such as, for example, spiro[3.3]heptane. The termspiroheterocycloalkyl, as used herein, means a spirocyclicheterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term C₁₋₆ acyl refers to a group—C(═O)R contain 6 carbon atoms. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “ester” as used herein denotes a group of formula —C(═O)ORwherein R is lower alkyl as defined herein.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″—, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkylene” or “alkylenyl” as used herein denotes a divalentsaturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g.,(CH₂)_(n)) or a branched saturated divalent hydrocarbon radical of 2 to10 carbon atoms (e.g., —CHMe- or —CH₂CH(i-Pr)CH₂—), unless otherwiseindicated. Except in the case of methylene, the open valences of analkylene group are not attached to the same atom. Examples of alkyleneradicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an-O-alkyl wherein alkyl is C₁₋₁₀.

The term “PCy₃” refers to a phosphine trisubstituted with three cyclicmoieties.

The terms “haloalkoxy” or “halo-lower alkoxy” or “lower haloalkoxy”refers to a lower alkoxy group, wherein one or more carbon atoms aresubstituted with one or more halogen atoms.

The term “hydroxyalkyl” or “hydroxyl lowe alkyl”, as used herein denotesan alkyl radical, or lower alkyl radical, as herein defined, wherein oneto three hydrogen atoms on different carbon atoms is/are replaced byhydroxyl groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The terms “alkylsulfonylamino” and “arylsulfonylamino” as used hereinrefers to a group of formula —NR′S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein.

The term “cycloalkyl” as used herein refers to a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “carboxy” or “carboxyl” refers to a —CO₂H moiety.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic or partially unsaturated ring containing four to eight atomsper ring, incorporating one or more N, O, or S heteroatoms, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic orpartially unsaturated ring. As well known to those skilled in the art,heteroaryl rings have less aromatic character than their all-carboncounter parts. Thus, for the purposes of the invention, a heteroarylgroup need only have some degree of aromatic character. Examples ofheteroaryl moieties include monocyclic aromatic heterocycles having 5 to6 ring atoms and 1 to 3 heteroatoms include, but is not limited to,pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, 4,5-Dihydro-oxazolyl,5,6-Dihydro-4H-[1,3]oxazolyl, isoxazole, thiazole, isothiazole,triazoline, thiadiazole and oxadiaxoline which can optionally besubstituted with one or more, preferably one or two substituentsselected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy,alkylthio, halo, lower haloalkyl, alkylsulfmyl, alkylsulfonyl, halogen,amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino andarylcarbonylamino. Examples of bicyclic moieties include, but are notlimited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl,5,6,7,8-Tetrahydro-[1,6]naphthyridinyl, and benzisothiazole. Bicyclicmoieties can be optionally substituted on either ring, however the pointof attachment is on a ring containing a heteroatom.

The term “heterocyclyl”, “heterocycloalkyl” or “heterocycle” as usedherein denotes a monovalent saturated cyclic radical, consisting of oneor more rings, preferably one to two rings, including spirocyclic ringsystems, of three to eight atoms per ring, incorporating one or morering heteroatoms (chosen from N,O or S(O)₀₋₂), and which can optionallybe independently substituted with one or more, preferably one or twosubstituents selected from hydroxy, oxo, cyano, lower alkyl, loweralkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl,pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, andionic forms thereof. Examples may also be bicyclic, such as, forexample, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane,or octahydro-pyrazino[2,1-c][1,4]oxazine.

Inhibitors of HCV NS5A

The application provides a compound of Formula I

wherein:

-   n is 1 or 2;-   Q is phenyl or naphthalene substituted with one or more Q′;

Q′ is hydroxyl, lower alkyl, or halo;

-   R¹ is lower alkyl, cycloalkyl, phenyl, or heterocycloalkyl;-   R² is —C(═O)OR^(2′), —C(═O)ON(R^(2′))₂, monocyclic or bicyclic    heteroaryl, optionally substituted with one or more R^(2′);

each R^(2′) is independently H, lower alkyl or heterocycloalkyl;

-   R³ is H or lower alkyl; and-   X is CH₂ or C(═O);-   or a pharmaceutically acceptable salt thereof.

The application provides a compound of Formula I, wherein n is 1.

The application provides a compound of Formula I, wherein R³ is H.

The application provides a compound of Formula I, wherein R³ is H and nis 1.

The application provides a compound of Formula I, wherein X is CH₂.

The application provides a compound of Formula I, wherein X is CH₂ andR³ is H.

The application provides a compound of Formula I, wherein X is CH₂ and nis 1.

The application provides a compound of Formula I, wherein X is CH₂, R³is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and R³ is H.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and X is CH₂.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² ismonocyclic or bicyclic heteroaryl, optionally substituted with one ormore R^(2′).

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′).

The application provides a compound of Formula I, wherein R^(2′) islower alkyl.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′) and R^(2′) is lower alkyl.

The application provides a compound of Formula I, wherein R² ismonocyclic or bicyclic heteroaryl, optionally substituted with one ormore R^(2′), X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′), X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R^(2′) islower alkyl, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′), R^(2′) is lower alkyl, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R¹ is loweralkyl or cycloalkyl.

The application provides a compound of Formula I, wherein R¹ iscyclohexyl.

The application provides a compound of Formula I, wherein R¹ is loweralkyl or cycloalkyl, R² is —C(═O)OR^(2′), R^(2′) is lower alkyl, X isCH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R¹ iscyclohexyl, R² is —C(═O)OR^(2′), R^(2′) is lower alkyl, X is CH₂, R³ isH, and n is 1.

The application provides a compound of Formula I, wherein n is 1.

The application provides a compound of Formula I, wherein R³ is H.

The application provides a compound of Formula I, wherein R³ is H and nis 1.

The application provides a compound of Formula 1, wherein X is CH₂.

The application provides a compound of Formula I, wherein X is CH₂ andR³ is H.

The application provides a compound of Formula I, wherein X is CH₂ and nis 1.

The application provides a compound of Formula I, wherein X is CH₂, R³is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and R³ is H.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂ and X is CH₂.

The application provides a compound of Formula I, wherein R² is—C(═O)N(R^(2′))₂, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² ismonocyclic or bicyclic heteroaryl, optionally substituted with one ormore R^(2′).

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′).

The application provides a compound of Formula I, wherein R^(2′) islower alkyl.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′) and R^(2′) is lower alkyl.

The application provides a compound of Formula I, wherein R² ismonocyclic or bicyclic heteroaryl, optionally substituted with one ormore R^(2′), X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′), X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R^(2′) islower alkyl, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R² is—C(═O)OR^(2′), R^(2′) is lower alkyl, X is CH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R¹ is lowerallcyl or cycloalkyl.

The application provides a compound of Formula I, wherein R¹ iscyclohexyl.

The application provides a compound of Formula I, wherein R¹ is loweralkyl or cycloalkyl, R² is —C(═O)OR^(2′), R^(2′) is lower alkyl, X isCH₂, R³ is H, and n is 1.

The application provides a compound of Formula I, wherein R¹ iscyclohexyl, R² is —C(═O)OR^(2′), R^(2′) is lower alkyl, X is CH₂, R³ isH, and n is 1.

The application provides a compound selected from the group consistingof:

-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid tent-butyl ester;-   (2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-yrrolidine-2-carboxylic    acid ethyl ester;-   1-Hydroxy-naphthalene-2-carboxylic acid    ((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide;-   (2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic    acid methyl ester;-   1 -Hydroxy-naphthalene-2-carboxylic acid    [(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;-   1-Hydroxy-naphthalene-2-carboxylic acid    [(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;-   1-Hydroxy-naphthalene-2-carboxylic acid    ((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid benzylamide;-   (2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid isopropylamide;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid propylamide;-   (2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethylamide;-   (2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic    acid ethylamide;-   (2R,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4S)-1-Cyclohexyhnethyl-4-[(1    -hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylic    acid methyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(8-hydroxy-quinoline-7-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid amide;-   1-Hydroxy-naphthalene-2-carboxylic acid    [(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide;-   (2S,4R)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid ethyl ester;-   (2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic    acid methyl ester; and-   1-Hydroxy-naphthalene-2-carboxylic acid    [(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amide.

The application provides a method for treating a Hepatitis C Virus (HCV)infection comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula 1.

The application provides the above method, further comprisingadministering an immune system modulator or an antiviral agent thatinhibits replication of HCV, or a combination thereof.

The application provides the above method, wherein the immune systemmodulator is an interferon or chemically derivatized interferon.

The application provides the above methods, wherein the antiviral agentis selected from the group consisting of a HCV protease inhibitor, a HCVpolymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor,a HCV fusion inhibitor, and a combination thereof.

The application provides a method for inhibiting replication of HCV in acell comprising administering a compound of any one of Formula 1.

The application provides a composition comprising a compound of FormulaI and a pharmaceutically acceptable excipient.

The application provides a use of the compound of Formula I in themanufacture of a medicament for the treatment of HCV.

The application provides a compound, composition, or method as describedherein.

Compounds

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOMTM v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

TABLE I depicts examples of compounds according to generic Formula I.

TABLE I # Structure Nomenclature Example # I-1 

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid tert- butyl ester  9I-2 

(2S,4S)-1-(3,3- Dimethyl-butyl)-4-[(1- hydroxy-naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid methyl ester  3 I-3 

(2S,4R)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- piperidine-2- carboxylic acid ethyl ester 24 I-4 

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid ethyl ester  8 I-5 

1-Hydroxy- naphthalene-2- carboxylic acid ((3S,5S)-5-benzooxazol-2-yl-1- cyclohexylmethyl- pyrrolidin-3-yl)-amide 29 I-6 

(2S,4R)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- piperidine-2- carboxylic acid methyl ester 23 I-7 

1-Hydroxy- naphthalene-2- carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5- (5-methyl-oxazol-2- yl)-pyrrolidin-3-yl]- amide 27I-8 

1-Hydroxy- naphthalene-2- carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5- (5-phenyl-oxazol-2- yl)-pyrrolidin-3-yl]- amide 28I-9 

1-Hydroxy- naphthalene-2- carboxylic acid ((3S,5S)-1-cyclohexylmethyl-5- oxazol-2-yl- pyrrolidin-3-yl)-amide 26 I-10

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid methyl ester  1 I-11

(2S,4S)-1-Benzyl-4- [(1-hydroxy- naphthalene-2- carbonyl)-amino]-pyrrolidine-2- carboxylic acid methyl ester  2 I-12

(2S,4S)-1- Cyclopentylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid ethyl ester  4 I-13

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid benzylamide 14 I-14

(2S,4S)-1- Cyclohexanecarbonyl- 4-[(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid ethyl ester  7 I-15

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid isopropylamide 13 I-16

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid propylamide 12 I-17

(2S,4S)-1- Cyclobutylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid ethyl ester  5 I-18

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid ethylamide 10 I-19

(2S,4R)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- piperidine-2- carboxylic acid ethylamide 25 I-20

(2R,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid methyl ester 18 I-21

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]-2- methyl-pyrrolidine-2- carboxylic acid methyl ester17 I-22

(2S,4S)-4-[(1- Hydroxy-naphthalene- 2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2- carboxylic acid ethyl ester  6 I-23

(2S,4S)-4-[(1-Amino- naphthalene-2- carbonyl)-amino]-1-cyclohexylmethyl- pyrrolidine-2- carboxylic acid methyl ester 21 I-24

(2S,4S)-1- Cyclohexylmethyl-4- [(8-hydroxy- quinoline-7-carbonyl)-amino]-pyrrolidine-2- carboxylic acid ethyl ester 22 I-25

(2S,4S)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid amide 16 I-26

1-Hydroxy- naphthalene-2- carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5- (pyrrolidine-1- carbonyl)-pyrrolidin- 3-yl]-amide 15I-27

(2S,4R)-1-Benzyl-4- [(1-hydroxy- naphthalene-2- carbonyl)-amino]-pyrrolidine-2- carboxylic acid ethyl ester 20 I-28

(2S,4R)-1- Cyclohexylmethyl-4- [(1-hydroxy- naphthalene-2-carbonyl)-amino]- pyrrolidine-2- carboxylic acid methyl ester 19 I-29

1-Hydroxy- naphthalene-2- carboxylic acid [(3S,5S)-5-(azetidine-1-carbonyl)-1- cyclohexylmethyl- pyrrolidin-3-yl]-amide 11

Synthesis General Schemes Synthesis—General Reaction Schemes

Compound 5 can be synthesized following the reactions outlined inScheme 1. Commercially available(2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester can be treated with p-toluenesulfonyl chloride understandard conditions to provide compound 1 (see for example, PCTWO2008/148689). Compound 1 can be treated with sodium azide understandard conditions to form compound 2 (see for example, PCTWO2008/148689). Compound 2 can be treated with trifluoroacetic acidunder standard Boc-group deprotection conditions to provide compound 3(see for example, PCT WO2008/148689). Compound 3 can be treated withcyclohexanecarbaldehyde and sodium triacetoxyborohydride under standardreductive amination conditions to provide compound 4 (see for example,PCT WO2008/148689). Compound 4 can be treated under standard azidereduction conditions to provide compound 5 (see for example, PCTWO2008/148689).

Compound 10 can be synthesized following the reactions outlined inScheme 2. Commercially available(2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester can be treated with p-toluenesulfonyl chloride understandard conditions to provide compound 6 (see for example, PCTWO2008/148689). Compound 6 can be treated with sodium azide understandard conditions to form compound 7 (see for example, PCTWO2008/148689). Compound 7 can be treated with trifluoroacetic acidunder standard Boc-group deprotection conditions to provide compound 8(see for example, PCT WO2008/148689). Compound 8 can be treated withcyclohexanecarbaldehyde and sodium triacetoxyborohydride under standardreductive amination conditions to provide compound 9 (see for example,PCT WO2008/148689). Compound 9 can be treated under standard azidereduction conditions to provide compound 10 (see for example, PCTWO2008/148689).

Compound 12 can be synthesized following the reactions outlined inScheme 3. Compound 3 can be treated with benzaldehyde and sodiumtriacetoxyborohydride under standard reductive amination conditions toprovide compound 11 (see for example, PCT WO2008/148689). Compound 11can be treated under standard azide reduction conditions to providecompound 12 (see for example, PCT WO2008/148689).

Compound 14 can be synthesized following the reactions outlined inScheme 4. Compound 3 can be treated with 3,3-dimethyl-butyraldehyde andsodium triacetoxyborohydride under standard reductive aminationconditions to provide compound 13 (see for example, PCT WO2008/148689).Compound 13 can be treated under standard azide reduction conditions toprovide compound 14 (see for example, PCT WO2008/148689).

Compound 16 can be synthesized following the reactions outlined inScheme 5. Compound 8 can be treated with cyclopentanecarbaldehyde andsodium triacetoxyborohydride under standard reductive aminationconditions to provide compound 15 (see for example, PCT WO2008/148689).Compound 15 can be treated under standard azide reduction conditions toprovide compound 16 (see for example, PCT WO2008/148689).

Compound 18 can be synthesized following the reactions outlined inScheme 6. Compound 8 can be treated with cyclobutanecarbaldehyde andsodium triacetoxyborohydride under standard reductive aminationconditions to provide compound 17 (see for example, PCT WO2008/148689).Compound 17 can be treated under standard azide reduction conditions toprovide compound 18 (see for example, PCT WO2008/148689).

Compound 20 can be synthesized following the reactions outlined inScheme 7. Compound 8 can be treated with isobutyraldehyde and sodiumtriacetoxyborohydride under standard reductive amination conditions toprovide compound 19 (see for example, PCT WO2008/148689). Compound 19can be treated under standard azide reduction conditions to providecompound 20 (see for example, PCT WO2008/148689).

Compound 22 can be synthesized following the reactions outlined inScheme 8. Compound 8 can be treated with cyclohexanecarbonyl chlorideunder standard amide coupling conditions to provide compound 21 (see forexample, Zanardi, F.; Burreddu, P.; Rassu, G.; Auzzas, L.; Battistini,L.; Curti, C.; Sartori, A.; Nicastro, G.; Menchi, G.; Cini, N.;Bottonocetti, A.; Raspanti, S.; Casiraghi, G. J. Med. Chem. 2008, 51,1771). Compound 21 can be treated under standard azide reductionconditions to provide compound 22 (see for example, PCT WO2008/148689).

Compound 27 can be synthesized following the reactions outlined inScheme 9. Commercially available(2S,4S)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester can be treated with p-toluenesulfonyl chloride understandard conditions to provide compound 23 (see for example, PCTWO2008/148689). Compound 23 can be treated with sodium azide understandard conditions to form compound 24 (see for example, PCTWO2008/148689). Compound 24 can be treated with trifluoroacetic acidunder standard Boc-group deprotection conditions to provide compound 25(see for example, PCT WO2008/148689). Compound 25 can be treated withcyclohexanecarbaldehyde and sodium triacetoxyborohydride under standardreductive amination conditions to provide compound 26 (see for example,PCT WO2008/148689). Compound 26 can be treated under standard azidereduction conditions to provide compound 27 (see for example, PCTWO2008/148689).

Compound 32 can be synthesized following the reactions outlined inScheme 10. Commercially available(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester can be treated with p-toluenesulfonyl chloride understandard conditions to provide compound 28 (see for example, PCTWO2008/148689). Compound 28 can be treated with sodium azide understandard conditions to form compound 29 (see for example, PCTWO2008/148689). Compound 29 can be treated with trifluoroacetic acidunder standard Boc-group deprotection conditions to provide compound 30(see for example, PCT WO2008/148689). Compound 30 can be treated withcyclohexanecarbaldehyde and sodium triacetoxyborohydride under standardreductive amination conditions to provide compound 31 (see for example,PCT WO2008/148689). Compound 31 can be treated under standard azidereduction conditions to provide compound 32 (see for example, PCTWO2008/148689).

Compound 37 can be synthesized following the reactions outlined inScheme 11. Commercially available(2S,4S)-4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester can be treated with p-toluenesulfonyl chloride understandard conditions to provide compound 33 (see for example, PCTWO2008/148689). Compound 33 can be treated with sodium azide understandard conditions to form compound 34 (see for example, PCTWO2008/148689). Compound 34 can be treated with trifluoroacetic acidunder standard Boc-group deprotection conditions to provide compound 35(see for example, PCT WO2008/148689). Compound 35 can be treated withcyclohexanecarbaldehyde and sodium triacetoxyborohydride under standardreductive amination conditions to provide compound 36 (see for example,PCTWO2008/148689). Compound 36 can be treated under standard azidereduction conditions to provide compound 37 (see for example, PCTWO2008/148689).

Compound 44 can be synthesized following the reactions outlined inScheme 12. Commercially available(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl estercan be coupled to 2,2-dimethoxy-ethylamine under standard amide couplingconditions to provide compound 38 (see for example, US 2007/0167426).Compound 38 can be treated with hydrochloric acid under standardconditions to form compound 39 (see for example, PCT WO2004/113353).Compound 39 can be treated with hexachloroethane and triphenylphosphineunder standard conditions to provide compound 40 (see for example, PCTWO2007/077004). Compound 40 can be treated with trifluoroacetic acidunder standard conditions to form compound 41 (see for example, PCTWO2007/106670). Compound 41 can be treated with p-toluenesulfonylchloride under standard conditions to provide compound 42 (see forexample, PCT WO2008/148689). Compound 42 can be treated with sodiumazide under standard conditions to form compound 43 (see for example,PCT WO2008/148689). Compound 43 can be treated under standard azidereduction conditions to provide compound 44 (see for example, PCTWO2008/148689).

Compound 50 can be synthesized following the reactions outlined inScheme 13. Commercially available(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl estercan be coupled to 1-amino-propan-2-one under standard amide couplingconditions to provide compound 45 (see for example, US 2007/0167426).Compound 45 can be treated with hexachloroethane and triphenylphosphineunder standard conditions to provide compound 46 (see for example, PCTWO2007/077004). Compound 46 can be treated with trifluoroacetic acidunder standard conditions to form compound 47 (see for example, PCTWO2007/106670). Compound 47 can be treated with p-toluenesulfonylchloride under standard conditions to provide compound 48 (see forexample, PCT WO2008/148689). Compound 48 can be treated with sodiumazide under standard conditions to form compound 49 (see for example,PCT WO2008/148689). Compound 49 can be treated under standard azidereduction conditions to provide compound 50 (see for example, PCTWO2008/148689).

Compound 56 can be synthesized following the reactions outlined inScheme 14. Commercially available(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl estercan be coupled to 1-amino-3,3-dimethyl-butan-2-one under standard amidecoupling conditions to provide compound 51 (see for example, US2007/0167426). Compound 51 can be treated with hexachloroethane andtriphenylphosphine under standard conditions to provide compound 52 (seefor example, PCT WO2007/077004). Compound 52 can be treated withtrifluoroacetic acid under standard conditions to form compound 53 (seefor example, PCT WO2007/106670). Compound 53 can be treated withp-toluenesulfonyl chloride under standard conditions to provide compound54 (see for example, PCT WO2008/148689). Compound 54 can be treated withsodium azide under standard conditions to form compound 55 (see forexample, PCT WO2008/148689). Compound 55 can be treated under standardazide reduction conditions to provide compound 56 (see for example, PCTWO2008/148689).

Compound 62 can be synthesized following the reactions outlined inScheme 15. Commercially available(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl estercan be coupled to 2-amino-1-phenyl-ethanone under standard amidecoupling conditions to provide compound 57 (see for example, US2007/0167426). Compound 57 can be treated with hexachloroethane andtriphenylphosphine under standard conditions to provide compound 58 (seefor example, PCT WO2007/077004). Compound 58 can be treated withtrifluoroacetic acid under standard conditions to fonn compound 59 (seefor example, PCT WO2007/106670). Compound 59 can be treated withp-toluenesulfonyl chloride under standard conditions to provide compound60 (see for example, PCT WO2008/148689). Compound 60 can be treated withsodium azide under standard conditions to form compound 61 (see forexample, PCT WO2008/148689). Compound 61 can be treated under standardazide reduction conditions to provide compound 62 (see for example, PCTWO2008/148689).

Compound 68 can be synthesized following the reactions outlined inScheme 16. Commercially available(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl estercan be coupled to 2-bromo-phenylamine under standard amide couplingconditions to provide compound 63 (see for example, US 2007/0167426).Compound 63 can be treated with copper (I) iodide and1,10-phenanthraline to provide compound 64 (see for example, Evindar,G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802). Compound 64 can betreated with trifluoroacetic acid under standard conditions to formcompound 65 (see for example, PCT WO2007/106670). Compound 65 can betreated with p-toluenesulfonyl chloride under standard conditions toprovide compound 66 (see for example, PCT WO2008/148689). Compound 66can be treated with sodium azide under standard conditions to formcompound 67 (see for example, PCT WO2008/148689). Compound 67 can betreated under standard azide reduction conditions to provide compound 68(see for example, PCT WO2008/148689).

Compound 74 can be synthesized following the reactions outlined inScheme 17. Commercially available(2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester can be treated with lithium diisopropylamide andiodomethane to provide compound 69 (see for example, Noe, C. R.;Knollmueller, M.; Voellenkle, H.; Noe-Letsching, M.; Weigand, A.; Muehl,J. Pharmazie, 1996, 51, 800). Compound 69 can be treated withp-toluenesulfonyl chloride under standard conditions to provide compound70 (see for example, PCT WO2008/148689). Compound 70 can be treated withsodium azide under standard conditions to form compound 71 (see forexample, PCT WO2008/148689). Compound 71 can be treated withtrifluoroacetic acid under standard Boc-group deprotection conditions toprovide compound 72 (see for example, PCT WO2008/148689). Compound 72can be treated with cyclohexanecarbaldehyde and sodiumtriacetoxyborohydride under standard reductive amination conditions toprovide compound 73 (see for example, PCT WO2008/148689). Compound 73can be treated under standard azide reduction conditions to providecompound 74 (see for example, PCT WO2008/148689).

Examples 1-7 can be synthesized following the reactions outlined inScheme 18. Commercially available 1-hydroxy-naphthalene-2-carboxylicacid can be treated with different amines (e.g. 5, 12, 14, 16, 18, 20and 22) under standard amide coupling conditions (e.g. HATU, HBTU) toafford examples 1-7 (see for example, PCT WO2010/009196).

Examples 8-16 can be synthesized following the reactions outlined inScheme 19. Commercially available 1-hydroxy-naphthalene-2-carboxylicacid can be treated with(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester (compound 5) under standard amide coupling conditions (e.g. HATU,HBTU) to afford example 1 (see for example, PCT WO2010/009196). Example1 can be treated with lithium hydroxide under standard ester hydrolysisconditions to afford compound 75 (see for example, WO2008/046527).Compound 75 can be treated under standard esterification conditions toafford examples 8-9 (see for example, Bellis, E.; Kokotos, G.Tetrahedron 2005, 61, 8669). Compound 75 can be treated under standardamide coupling conditions (e.g. HATU, HBTU, see for example PCTWO2010/009196) to afford examples 10-16.

Examples 17-20 can be synthesized following the reactions outlined inScheme 20. Commercially available 1-hydroxy-naphthalene-2-carboxylicacid can be treated with different amines (e.g. 27, 32 and 74) understandard amide coupling conditions (e.g. HATU, HBTU) to afford examples17-20 (see for example, PCT WO2010/009196).

Examples 21-22 can be synthesized following the reactions outlined inScheme 19. (2S,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylicacid methyl ester (compound 5) can be treated with commerciallyavailable 1-amino-naphthalene-2-carboxylic acid or8-hydroxy-quinoline-7-carboxylic acid under standard amide couplingconditions (e.g. HATU, HBTU) to afford examples 21-22 (see for example,PCT WO2010/009196).

Examples 23-25 can be synthesized following the reactions outlined inScheme 22. Commercially available l-hydroxy-naphthalene-2-carboxylicacid can be treated with(2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methylester (compound 37) under standard amide coupling conditions (e.g. HATU,HBTU) to afford example 23 (see for example, PCT WO2010/009196). Example23 can be treated with lithium hydroxide under standard ester hydrolysisconditions to afford compound 76 (see for example, PCT WO2008/046527).Compound 76 can be treated under standard esterification conditions toafford example 24 (see for example, Bellis, E.; Kokotos, G. Tetrahedron2005, 61, 8669). Compound 76 can be treated under standard amidecoupling conditions (e.g. HATU, HBTU, see for example PCT WO2010/009196)to afford example 25.

Examples 26-29 can be synthesized following the reactions outlined inScheme 23. Commercially available 1-hydroxy-naphthalene-2-carboxylicacid can be treated with different amines (e.g. compounds 44, 50, 56, 62and 68) under standard amide coupling conditions (e.g. HATU, HBTU) toafford compound 77 (see for example, PCT WO2010/009196). Compound 77 canbe treated with hydrogen under standard metal catalyzed deprotectionconditions to afford compound 78 (see for example, Chang, D.; Heringa,M. F.; Witholt, B.; Li, Z. J. Org. Chem. 2003, 68, 8599). Compound 78can be treated with cyclohexanecarbaldehyde and sodiumtriacetoxyborohydride under standard reductive amination conditions toprovide Examples 26-29 (see for example, PCT WO2008/148689).

Pharmaceutical Compositions and Administration

Pharmaceutical compositions of the subject Compounds for administrationvia several routes were prepared as described in this Example.

Composition for Oral Administration (A)

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration (B)

Ingredient % wt/wt. Active ingredient 20.0% Magnesium stearate 0.5%Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine)1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration (C)

Ingredient % wt./wt. Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation (D)

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to makeisotonic Water for injection to 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Dosage and Administration:

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatin capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyObenzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell-known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichiorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pennsylvania. A skilled formulation scientist maymodify the formulations within the teachings of the specification toprovide numerous formulations for a particular route of administrationwithout rendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Indications and Method of Treatment Indications

The compounds of the invention and their isomeric forms andpharmaceutically acceptable salts thereof are useful in treating andpreventing HCV infection.

The application provides a method for treating a Hepatitis C Virus (HCV)infection comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula I.

The application provides a method for inhibiting replication of HCV in acell comprising administering a compound of Formula I.

Combination Therapy

The compounds of the invention and their isomeric forms andpharmaceutically acceptable salts thereof are useful in treating andpreventing HCV infection alone or when used in combination with othercompounds targeting viral or cellular elements or functions involved inthe HCV lifecycle. Classes of compounds useful in the invention include,without limitation, all classes of HCV antivirals.

For combination therapies, mechanistic classes of agents that can beuseful when combined with the compounds of the invention include, forexample, nucleoside and non-nucleoside inhibitors of the HCV polymerase,protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinalagents that functionally inhibit the internal ribosomal entry site(IRES) and other medicaments that inhibit HCV cell attachment or virusentry, HCV RNA translation, HCV RNA transcription, replication or HCVmaturation, assembly or virus release. Specific compounds in theseclasses and useful in the invention include, but are not limited to,macrocyclic, heterocyclic and linear HCV protease inhibitors such astelaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-9005 18),ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BI-201335,BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095 (HCV NS4A proteaseco-factor inhibitor), VX-500, VX-8 13, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-0 13420 (and congeners) and VBY-376; the Nucleosidic HCVpolymerase (replicase) inhibitors useful in the invention include, butare not limited to, R7128, PSI-785 1, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleoside andnucleotide analogs and HCV inhibitors including (but not limited to)those derived as 2′-C-methyl modified nucleos(t)ides, 4′-aza modifiednucleos(t)ides, and 7′-deaza modified nucleos(t)ides. Non-nucleosidicHCV polymerase (replicase) inhibitors useful in the invention, include,but are not limited to, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222,ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190,A-837093, JKT-109, GL-59728 and GL-60667.

In addition, compounds of the invention can be used in combination withcyclophyllin and immunophyllin antagonists (e.g., without limitation,DEBIO compounds, NM-811 as well as cyclosporine and its derivatives),kinase inhibitors, inhibitors of heat shock proteins (e.g., HSP90 andHSP70), other immunomodulatory agents that can include, withoutlimitation, interferons (-alpha, -beta, -omega, -gamma, -lambda orsynthetic) such as Intron A, Roferon-A, Canferon-A300, Advaferon,Infergen, Hunioferon, Sumiferon MP, Alfaferone, Feron and the like;polyethylene glycol derivatized (pegylated) interferon compounds, suchas PEG interferon-α-2a (Pegasys), PEG interferon-α-2b (PEGIntron),pegylated IFN-α-conl and the like; long acting formulations andderivatizations of interferon compounds such as the albumin-fusedinterferon, Albuferon, Locteron, and the like; interferons with varioustypes of controlled delivery systems (e.g., ITCA-638, omega-interferondelivered by the DUROS subcutaneous delivery system); compounds thatstimulate the synthesis of interferon in cells, such as resiquimod andthe like; interleukins; compounds that enhance the development of type Ihelper T cell response, such as SCV-07 and the like; TOLL-like receptoragonists such as CpG-10101 (actilon), isotorabine, ANA773 and the like;thymosin α-1; ANA-245 and ANA-246; histamine dihydrochloride;propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000;antibodies, such as civacir, XTL-6865 and the like and prophylactic andtherapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like. Inaddition, any of the above-described methods involving administering anNS5A inhibitor, a Type I interferon receptor agonist (e.g., an IFN-α)and a Type II interferon receptor agonist (e.g., an IFN-γ) can beaugmented by administration of an effective amount of a TNF-αantagonist. Exemplary, non-limiting TNF-α antagonists that are suitablefor use in such combination therapies include ENBREL, REMICADE, andHUMIRA.

In addition, compounds of the invention can be used in combination withantiprotozoans and other antivirals thought to be effective in thetreatment of HCV infection such as, without limitation, the prodrugnitazoxanide. Nitazoxanide can be used as an agent in combination withthe compounds disclosed in this invention as well as in combination withother agents useful in treating HCV infection such as peginterferon α-2aand ribavirin.

Compounds of the invention can also be used with alternative forms ofinterferons and pegylated interferons, ribavirin or its analogs (e.g.,tarabavarin, levoviron), microRNA, small interfering RNA compounds(e.g., SIRPLEX-140-N and the like), nucleotide or nucleoside analogs,immunoglobulins, hepatoprotectants, anti-inflammatory agents and otherinhibitors of NS5A. Inhibitors of other targets in the HCV lifecycleinclude NS3 helicase inhibitors; NS4A co-factor inhibitors; antisenseoligonucleotide inhibitors, such as ISIS-14803, AVI-4065 and the like;vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such asheptazyme, RPI, 13919 and the like; entry inhibitors such as HepeX-C,HuMax-HepC and the like; alpha glucosidase inhibitors such ascelgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 and IMPDHinhibitors. Other illustrative HCV inhibitor compounds include thosedisclosed in the following publications: U.S. Pat. Nos. 5,807,876;6,498,178; 6,344,465; and 6,054,472; PCT Patent Application PublicationNos. WO97/40028; WO98/40381; WO00/56331, WO02/04425; WO03/007945;WO03/010141; WO03/000254; WO01/32153; WO00/06529; WO00/18231;WO00/10573; WO00/13708; WO01/85172; WO03/037893; WO03/037894;WO03/037895; WO02/100851; WO02/100846; WO99/01582; WO00/09543;WO02/18369; WO98/17679, WO00/056331; WO98/22496; WO99/07734;WO05/073216, WO05/073195 and WO08/021927.

Additionally, combinations of, for example, ribavirin and interferon,may be administered as multiple combination therapy with at least one ofthe compounds of the invention. The present invention is not limited tothe aforementioned classes or compounds and contemplates known and newcompounds and combinations of biologically active agents. It is intendedthat combination therapies of the present invention include anychemically compatible combination of a compound of this inventive groupwith other compounds of the inventive group or other compounds outsideof the inventive group, as long as the combination does not eliminatethe anti-viral activity of the compound of this inventive group or theanti-viral activity of the pharmaceutical composition itself.

Combination therapy can be sequential, that is treatment with one agentfirst and then a second agent (for example, where each treatmentcomprises a different compound of the invention or where one treatmentcomprises a compound of the invention and the other comprises one ormore biologically active agents) or it can be treatment with both agentsat the same time (concurrently). Sequential therapy can include areasonable time after the completion of the first therapy beforebeginning the second therapy. Treatment with both agents at the sametime can be in the same daily dose or in separate doses. Combinationtherapy need not be limited to two agents and may include three or moreagents. The dosages for both concurrent and sequential combinationtherapy will depend on absorption, distribution, metabolism andexcretion rates of the components of the combination therapy as well asother factors known to one of skill in the art. Dosage values will alsovary with the severity of the condition to be alleviated. It is to befurther understood that for any particular subject, specific dosageregimens and schedules may be adjusted over time according to theindividual's need and the judgment of the one skilled in the artadministering or supervising the administration of the combinationtherapy.

The application provides a method for treating a Hepatitis C Virus (HCV)infection comprising administering to a patient in need thereof atherapeutically effective amount of a compound of any one of FormulaeI-IIII.

The application provides the above method, further comprisingadministering an immune system modulator or an antiviral agent thatinhibits replication of HCV, or a combination thereof.

The application provides the above method, wherein the immune systemmodulator is an interferon or chemically derivatized interferon.

The application provides the above methods, wherein the antiviral agentis selected from the group consisting of a HCV protease inhibitor, a HCVpolymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor,a HCV fusion inhibitor, and a combination thereof.

EXAMPLES Abbreviations

Commonly used abbreviations include: acetyl (Ac),azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm),9-borabicyclo[3.3.1]nonane (9-BBN or BBN),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tert-butoxycarbonyl(Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC₂O), benzyl(Bu), butyl (Bu), Chemical Abstracts Registration Number (CASRN),benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI),1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride(DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE),dichloromethane (DCM), 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),diethyl azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine(DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),1,1′-bis-(diphenylphosphino)ethane (dppe),1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), ethyl (Et), ethylacetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acidethyl ester (EEDQ), diethyl ether (Et₂O), ethyl isopropyl ether(EtOiPr), O-(7-azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), isopropylmagnesium chloride (iPrMgCl),hexamethyl disilazane (HMDS), liquid chromatography mass spectrometry(LCMS), lithium hexamethyl disilazane (LiHMDS), meta-chloroperoxybenzoicacid (m-CPBA), methanol (MeOH), melting point (mp), MeSO₂— (mesyl orMs), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA),mass spectrum (ms), methyl t-butyl ether (MTBE), methyl tetrahydrofuran(MeTHF), N-bromosuccinimide (NBS), n-Butyllithium (nBuLi),N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine(NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC),Dichloro-((bis-diphenylphosphino)ferrocenyl)palladium(II) (Pd(dppf)Cl₂),palladium(II) acetate (Pd(OAc)₂),tris(dibenzylideneacetone)dipalladium(O) (Pd₂(dba)₃), pyridiniumdichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), poundsper square inch (psi), pyridine (pyr),1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos),room temperature (ambient temperature, rt or RT), sec-Butyllithium(sBuLi), tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS),tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et₃N),2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF₃SO₂— (TI),trifluoroacetic acid (TFA),1,1′-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF),trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOHor pTsOH), 4-Me-C₆H₄SO₂— or tosyl (Ts), andN-urethane-N-carboxyanhydride (UNCA). Conventional nomenclatureincluding the prefixes normal (n), iso (i-), secondary (sec-), tertiary(tert-) and neo have their customary meaning when used with an alkylmoiety. (J. Rigaudy and D. P. Klesney, Nomenclature in OrganicChemistry, IUPAC 1979 Pergamon Press, Oxford.).

General Conditions

Compounds of the invention can be made by a variety of methods depictedin the illustrative synthetic reactions described below in the Examplessection.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. It should beappreciated that the synthetic reaction schemes shown in the Examplessection are merely illustrative of some methods by which the compoundsof the invention can be synthesized, and various modifications to thesesynthetic reaction schemes can be made and will be suggested to oneskilled in the art having referred to the disclosure contained in thisapplication.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein aretypically conducted under an inert atmosphere at atmospheric pressure ata reaction temperature range of from about −78° C. to about 150° C.,often from about 0° C. to about 125° C., and more often and convenientlyat about room (or ambient) temperature, e.g., about 20° C.

Various substituents on the compounds of the invention can be present inthe starting compounds, added to any one of the intermediates or addedafter formation of the final products by known methods of substitutionor conversion reactions. If the substituents themselves are reactive,then the substituents can themselves be protected according to thetechniques known in the art. A variety of protecting groups is known inthe art, and can be employed. Examples of many of the possible groupscan be found in “Protective Groups in Organic Synthesis” by Green etal., John Wiley and Sons, 1999. For example, nitro groups can be addedby nitration and the nitro group can be converted to other groups, suchas amino by reduction, and halogen by diazotization of the amino groupand replacement of the diazo group with halogen. Acyl groups can beadded by Friedel-Crafts acylation. The acyl groups can then betransformed to the corresponding alkyl groups by various methods,including the Wolff-Kishner reduction and Clemmenson reduction. Aminogroups can be alkylated to form mono- and di-alkylamino groups; andmercapto and hydroxy groups can be alkylated to form correspondingethers. Primary alcohols can be oxidized by oxidizing agents known inthe art to form carboxylic acids or aldehydes, and secondary alcoholscan be oxidized to form ketones. Thus, substitution or alterationreactions can be employed to provide a variety of substituentsthroughout the molecule of the starting material, intermediates, or thefinal product, including isolated products.

PREPARATIVE EXAMPLES Preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester

Step 1: Preparation of(2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester

To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (10 g, 40.77 mmol) in methylenechloride (56 mL) at 0° C. was added pyridine (30 mL), followed bydropwise addition of a solution of p-toluenesulfonyl chloride (9.4 g,49.30 mmol) in methylene chloride. The reaction mixture was warmed toroom temperature and then refluxed for 16 h. The reaction mixture wasconcentrated, re-dissolved in methylene chloride, and washed with waterand brine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to give(2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (14.4 g, 88.4% yield) as a lightyellow sticky solid. The crude was used in the next step without furtherpurification. MS calcd. for C₁₈H₂₆NO₇S [(M+H)⁺] 400.0, obsd. 400.0.

Step 2: Preparation of (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester

To a solution of(2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (14.4 g, 36.09 mmol) in dryN,N-dimethylformamide (50 mL) was added sodium azide (4.7 g, 72.18 mmol)and the reaction mixture was stirred at 60° C. for 16 h. The reactionmixture was diluted with ethyl acetate, washed with water, brine, anddried over anhydrous sodium sulfate. Filtration and concentration gave acrude which was purified by column chromatography (15% ethyl acetate inhexane as eluent) to give (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylicacid 1-tent-butyl ester 2-methyl ester (7.8 g, 80% yield) as a lightbrown liquid. MS calcd. for C₁₁H₁₉N₄O₄[(M+H)⁺] 271.0, obsd. 271.0.

Step 3: Preparation of (2S,4S)-4-azido-pyrrolidine-2-carboxylic acidmethyl ester trifluoroacetate salt

To a solution of (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (7.8 g, 28.8 mmol) in methylenechloride (30 mL) was added a mixture of trifluoroacetic acid andmethylene chloride (1:5, 20 mL) and the reaction mixture was stirred atroom temp. for 16 h. The reaction mixture was concentrated under reducedpressure to give (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methylester trifluoroacetate salt (9.6 g, crude) as a light brown oil. Thecompound was used in the next step without further purification. MScalcd. for C₆H₁₁N₄O₂ [(M+H)⁺] 171.0, obsd. 171.2.

Step 4: Preparation of(2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester

To a solution of (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methylester trifluoro-acetate salt (9.6 g, 33.08 mmol) in 60 mLdichloromethane were added cyclohexanecarbaldehyde (2.6 g, 23.66 mmol),acetic acid (2.5 mL) and sodium triacetoxyborohydride (14.2 g, 66.16mmol) and the reaction mixture was stirred at room temp. for 20 h. Thereaction mixture was diluted with dichloromethane, washed with water,dried over anhydrous sodium sulfate and concentrated to give(2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester (11.2 g, crude) as a light brown liquid. The compound was used inthe next step without further purification. MS caled. for C₁₃H₂₃N₄O₂[(M+H)⁺] 267.0, obsd. 267.2.

Step 5: Preparation of(2S,4S)-4-amino-1-cyclohexylmethyI-pyrrolidine-2-carboxylic acid methylester

To a solution of(2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester (11.2 g, 42.1 mmol) in tetrahydrofuran (140 mL) were addedtriphenyl phosphine (22 g, 83.87 mmol) and water (1.9 mL) and thereaction mixture was refluxed at 75° C. for 6 h. The reaction mixturewas diluted with ether, quenched with HCl (0.15 N), stirred for 5 minand extracted with ether. The aqueous layer was treated with sodiumbicarbonate solution until pH˜10 and then extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate and concentrated to give(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester (3 g, 29.6% yield) as a light yellow oil. The compound was used inthe next step without further purification. MS calcd. for C₁₃H₂₅N₂O₂[(M+H)⁺] 241.0, obsd. 240.8.

Preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ethylester

(2S,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ethylester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acidethyl ester trifluoroacetate salt in a similar reaction sequence used inthe preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₄H₂₇N₂O₂ [(M+H)⁺] 255, obsd. 255.

Preparation of (2S,4S)-4-amino-1-benzyl-pyrrolidine-2-carboxylic acidmethyl ester

(2S,4S)-4-Amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester wasprepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl estertrifluoroacetate salt in a similar reaction sequence used in thepreparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₃H₁₉N₂O₂ {(M+H)⁺} 235, obsd. 235.

Preparation of(2S,4S)-4-amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acidmethyl ester

(2S,4S)-4-Amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acidmethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylicacid methyl ester trifluoroacetate salt in a similar reaction sequenceused in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₂H₂₅N₂O₂ [(M+H)⁺] 229, obsd. 229.

Preparation of(2S,4S)-4-amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ethylester

(2S,4S)-4-Amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid methylester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acidethyl ester trifluoroacetate salt in a similar reaction sequence used inthe preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₃H₂₅N₂O₂ [(M+H)⁺] 241, obsd. 241.

Preparation of(2S,4S)-4-amino-1-cyclobutylmethyl-pyrrolidine-2-carboxylic acid ethylester

(2S,4S)-4-Amino-1-cyclobutylmethyl-pyrrolidine-2-carboxylic acid ethylester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acidethyl ester trifluoroacetate salt in a similar reaction sequence used inthe preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₂H₂₃N₂O₂ [(M+H)⁺] 227, obsd. 227.

Preparation of (2S,4S)-4-amino-1-isobutyl-pyrrolidine-2-carboxylic acidethyl ester

(2S,4S)-4-Amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester wasprepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl estertrifluoroacetate salt in a similar reaction sequence used in thepreparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₁H₂₃N₂O₂ [(M+H)⁺] 215, obsd. 215.

Preparation of(2S,4S)-4-amino-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acidethyl ester

(2S,4S)-4-Amino-1-eyelohexanecarbonyl-pyrrolidine-2-carboxylic acidethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylicacid methyl ester trifluoroacetate salt in a similar reaction sequenceused in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₄H₂₅N₂O₃ [(M+H)⁺] 269, obsd. 269.

Preparation of(2S,4R)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester

(2S,4R)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester was prepared from (2S,4S)-4-hydroxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester in a similar reaction sequenceused in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₃H₂₅N₂O₂ [(M+H)⁺] 241, obsd. 241.

Preparation of(2R,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester

(2R,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester was prepared from (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester in a similar reaction sequenceused in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₃H₂₅N₂O₂ [(M+H)⁺] 241, obsd. 241.

Preparation of(2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methylester

(2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methylester was prepared from (2S,4S)-4-hydroxy-piperidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester in a similar reaction sequenceused in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS caled. for C₁₄H₂₇N₂O₂ [(M+H)⁺] 255, obsd. 255.

Preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylicacid benzyl ester

Step 1: Preparation of(2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester

To a stirred solution of(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester(500 mg, 1.56 mmol) and 2,2-dimethoxy-ethylamine (163 mg, 1.56 mmol) indichloromethane (5 mL) were added EDC-HCl (298 mg, 1.56 mmol), HOBt (210mg, 1.56 mmol) and triethylamine (157 mg, 1.56 mmol). The mixture wasstirred at room temp. for 24 h, diluted with water, extracted with ethylacetate and washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered, concentrated and purified bycolumn chromatography (using 15% EtOAc in hexane as eluent) to give(2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (200 mg, 31.6% yield) as a light brownliquid. MS calcd. for C₂₁H₃₃N₂O₆ [(M+H)⁺] 409.0, obsd. 409.0.

Step 2: Preparation of(2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester

A mixture of(2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester (1.8 g, 4.41 mmol) and HCl (1M, 30 mL) in acetone (30mL) was stirred at room temp. for 8 h. The reaction mixture was thenextracted with ethyl acetate and washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give(2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester (1.4 g, crude) as a sticky liquid. The compound wasused in the next step without further purification. MS calcd. forC_(l9)H₂₇N₂O₅ [(M+H)⁺] 363.0, obsd. 363.2.

Step 3: Preparation of(2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester

To a stirred solution of(2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester (4.5 g, 12.43 mmol) and hexachloroethane (5.88 g,24.86 mmol) in dichloromethane (30 mL) was added triphenyl phosphine(6.52 g, 24.86 mmol) The mixture was stirred at 0° C. for 15 min,triethylamine (2.5 g, 24.86 mmol) was then added and the mixture wasstirred at room temp. for 14 h. The reaction mixture was then extractedwith dichloromethane and washed with water and brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated. The residuewas purified by column chromatography (using 15% EtOAc in hexane aseluent) to give(2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester (2 g, 46.6% yield) as a yellow liquid. MS calcd. for C₁₉H₂₅N₂O₄[(M+H)⁺] 345.0, obsd. 345.2.

Step 4-7: Preparation of(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester

(2S,4S)-4-Amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl esterwas prepared from(2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester in a similar reaction sequence used in the preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₁₅H₁₈N₃O₃ [(M+H)⁺] 288, obsd. 288.

Preparation of(2S,4S)-4-amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester

Step 1: Preparation of(2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester

To a stirred solution of(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester(10.78 g, 33.54 mmol) and 1-amino-propan-2-one (2.45 g, crude, 33.54mmol) in dichlormethane (56 mL) were added EDC.HCl (6.405 g, 33.54mmol), HOBt (5.128 g, 33.54 mmol) and triethylamine (12.67 mL, 100.62mmol). The mixture was stirred at room temp. for 24 h. The reactionmixture was then diluted with water, extracted with dichloromethane andwashed with water and brine. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated. The crude was then purifiedby column chromatography to give(2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester (7 g, 55.4% yield) as a light brown liquid. MS calcd.for C₂₀H₂₉N₂O₅ [(M+H)⁺] 377.0, obsd. 377.4.

Step 2: Preparation of(2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester

To a stirred solution of(2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester (2.5 g, 6.65 mmol) and hexachloroethane (3.148 g, 13.3mmol) in dichloromethane (16 mL) was added triphenyl phosphine (3.458 g,13.3 mmol). The mixture was stirred at 0° C. for 20 min. Thentriethylamine (1.36 mL, 13.3 mmol) was added and the reaction mixturewas stirred at room temp. for 14 h. Water was then added to the reactionmixture, extracted with dichloromethane and the combined organic layerwas washed with water and brine. The organic layer was dried overanhydrous sodium sulfate and concentrated. The crude was then purifiedby column chromatography to give(2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester (1 g, 42% yield) as an off-white solid. MS calcd. forC₂₀H₂₇N₂O₄ [(M+H)⁺] 359.0, obsd. 359.0.

Step 3: Preparation of(2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester

To a stirred solution of(2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester (2 g, 5.59 mmol) in dichloromethane (15 mL) was addedtrifluoroacetic acid (1.57 mL) in dichloromethane (1:5) at 0° C. and themixture was then stirred at room temp. for 16 h. The reaction mixturewas neutralized with saturated sodium bicarbonate solution and extractedwith dichloromethane. The organic layer was washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude was then purified by column chromatography to give(2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester (1.1 g, 65.1% yield) as an off white solid. MS calcd. forC₁₆H₁₉N₂O₄ [(M+H)⁺] 303.0, obsd. 303.4.

Step 4-6: Preparation of(2S,4S)-4-amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester

(2S,4S)-4-Amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester was prepared from(2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester in a similar reaction sequence used in the preparation of(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester. MS calcd. for C₁₆H₂₀N₃O₃ [(M+H)⁺] 302, obsd. 302.

Preparation of(2S,4S)-4-amino-2-(5-tert-butyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4S)-4-Amino-2-(5-tert-butyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester was prepared from(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl esterin a similar reaction sequence used in the preparation of(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester. MS calcd. for C₁₉H₂₆N₃O₃ [(M+H)⁺] 344, obsd. 344.

Preparation of(2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester

(2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester was prepared from(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl esterin a similar reaction sequence used in the preparation of(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester. MS calcd. for C₂₁H₂₂N₃O₃ [(M+H)⁺] 364, obsd. 364.

Preparation of(2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester

Step 1: Preparation of(2S,4R)-2-(2-bromo-phenylcarbamoyl)-4-tert-butoxy-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4R)-2-(2-Bromo-phenylcarbamoyl)-4-tert-butoxy-pyrrolidine-1-carboxylicacid benzyl ester (290 mg, 19.6% purity) was synthesized from 1 g of(2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl esterfollowing the procedures described for(2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylicacid benzyl ester.

Step 2: Preparation of(2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acidbenzyl ester

To a stirred solution of(2S,4R)-2-(2-bromo-phenylcarbamoyl)-4-tert-butoxy-pyrrolidine-1-carboxylicacid benzyl ester (900 mg, 1.89 mmol) in DME (20 mL) at 25° C. in asealed tube were added CuI (36 mg, 0.19 mmol), 1,10-phenanthraline (68mg, 0.38 mmol), and Cs₂CO₃ (1.847 g, 5.68 mmol). The reaction mixturewas refluxed for 14 h. After completion of reaction, water was added,and the mixture was then extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude was thenpurified by column chromatography to give(2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acidbenzyl ester (430 mg, 57.5% yield) as a yellowish liquid. MS calcd. forC₂₃H₂₇N₂O₄ [(M+H)⁺] 395, obsd. 395.

Step 3-6: Preparation of(2S,4S)-4-amino-2-benzooxazoi-2-yl-pyrrolidine-1-carboxylic acid benzylester

(2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester was prepared from(2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acidbenzyl ester in a similar reaction sequence used in the preparation of(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester. MS calcd. for C₁₉H₂₀N₃O₃ [(M+H)⁺] 338, obsd. 338.

Preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylicacid methyl ester

Step 1: Preparation of(2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester

To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (500 mg, 2.04 mmol) and MeI (1.2 g,8.45 mmol) in tetrahydrofuran at −40° C. was added a solution of lithiumdiisopropylamide in tetrahydrofuran (1.5M solution, 5 mL, 7.47 mmol).The reaction mixture was warmed to room temp. and stirred for 4 h. Aftercompletion of reaction, the mixture was re-cooled to −30° C. andquenched with saturated aqueous ammonium chloride. The reaction mixturewas then extracted with ethyl acetate and washed with water and brine.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by preparative HPLC to give twostereoisomers; (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester (200 mg, 37.7% yield) and(2R,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (100 mg, 18.9% yield). MS calcd. forC₁₂H₂₂NO₅ [(M+H)⁺] 260, obsd. 260.

Steps 2-5: Preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylicacid methyl ester

(2S,4S)-4-Amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester in a similar reaction sequence used inthe preparation of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester.

Example 1(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester

To a stirred solution of(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester (150 mg, 0.62 mmol) and 1-hydroxy-naphthalene-2-carboxylic acid(90 mg, 0.75 mmol) in DMF (2 mL) were added HATU (285 mg, 0.75 mmol) andN,N-diisopropylethylamine (96 mg, 0.75 mmol). The mixture was stirred atroom temp. for 24 h. The reaction mixture was then extracted with ethylacetate and washed with water and brine. The organic layer was thendried over anhydrous sodium sulfate, concentrated and purified by columnchromatography to give(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester. MS calcd. for C₂₄H₃₁N₂O₄ [(M+H)⁴] 411.0, obsd. 411.0.

Example 2(2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester

(2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4S)-4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester and1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner toexample 1. MS calcd. for C₂₄H₂₅N₂O₄ [(M+H)⁺] 405.0, obsd. 405.0.

Example 3(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester

(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4S)-4-amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acidmethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogousmanner to example 1. MS calcd. for C₂₃H₃₁N₂O₄ [(M+H)⁺] 399.0, obsd.399.0.

Example 4(2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester was prepared from(2S,4S)-4-amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ethylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₄H₃₁N₂O₄ [(M+H)⁺] 411.0, obsd. 411.2.

Example 5(2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester was prepared from(2S,4S)-4-amino-1-cyclobutylmethyl-pyrrolidine-2-carboxylic acid ethylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₃H₂₉N₂O₄[(M+H)⁺] 397.0, obsd. 397.2.

Example 6(2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylicacid ethyl ester was prepared from(2S,4S)-4-amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester and1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner toexample 1. MS calcd. for C₂₂H₂₉N₂O₄ [(M+H)⁺] 385.0, obsd. 385.4.

Example 7(2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]pyrrolidine-2-carboxylicacid ethyl ester was prepared(2S,4S)-4-amino-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acidethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogousmanner to example 1. MS calcd. for C₂₅H₃₁N₂O₅ [(M+H)⁺] 439.0, obsd.439.4.

EXAMPLE 8(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

Step 1: Preparation of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid

To a stirred solution of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester (350 mg, 0.85 mmol) in methanol (8 mL) was addedlithium hydroxide (204 mg, 8.53 mmol) and the mixture was stirred atroom temp. for 24 h. The reaction mixture was then acidified with dilutehydrochloric acid, extracted with ethyl acetate and washed with waterand brine. The organic layer was dried over anhydrous sodium sulfate,filtered, concentrated and purified by column chromatography (using 15%EtOAc in hexane as eluent) to give(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid (250 mg, 74.0% yield) as a white solid. MS caled. forC₂₃H₂₉N₂O₄[(M+H)⁺] 397.0, obsd. 397.6.

Step 2:(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

To a stirred solution of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid (50 mg, 0.13 mmol) in ethanol (3 mL) was added conc. sulfuric acid(0.1 mL) and the reaction mixture was stirred at 95° C. for 14 h. Thereaction mixture was then concentrated under vacuum, diluted with water,extracted with ethyl acetate and washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered,concentrated and purified by column chromatography (using 5% EtOAc inhexane as eluent) to give(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester (28 mg, 52.3% yield) as a blue sticky liquid. MS calcd.for C₂₅H₃₃N₂O₄ [(M+H)⁺] 425.0, obsd. 425.2.

Example 9(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid tert-butyl ester

A mixture of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid (50 mg, 0.13 mmol) and 2,2,2-trichloro-acetimidic acid tert-butylester (70 mg, 0.33 mmol) in THF (1 mL) was stirred at 0° C. for severalminutes. Then BF₃.OEt₂ (20 mg, 0.13 mmol) was added dropwise at 0° C.and the reaction mixture was warmed to room temp. and stirred for 2 h.The reaction mixture was then quenched with brine solution, extractedwith ethyl acetate and washed with water and brine. The organic layerwas dried over anhydrous sodium sulfate, concentrated and purified bycolumn chromatography (using 5% EtOAc in hexane as eluent) to give(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid tert-butyl ester (20 mg, 35.0% yield) as a bluish sticky liquid. MScalcd. for C₂₇H₃₇N₂O₄ [(M+H)⁺] 453.0, obsd. 453.2.

Example 10(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethylamide

(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethylamide was prepared from(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid and ethylamine in an analogous manner to example 1. MS calcd. forC₂₅H₃₄N₃O₃ [(M+H)⁺] 424.0, obsd. 424.0.

Example 11 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amide

Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amidewas prepared from(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid and azetidine in an analogous manner to example 1. MS calcd forC₂₆H₃₄N₃O₃ [(M+H)⁺] 436.0, obsd. 436.0.

Example 12(2S,4S)-1-Cyclohexylmethyl-4-[1(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid propylamide

To a mixture of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester (150 mg, 0.37 mmol) and 44 mg of n-propyl amine wasadded Me₃Al (catalytic amount, 2M in toluene) under an argon atmospherein a seal tube and the mixture was heated at 100° C. for 16 hr. Thereaction mixture was then quenched with water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated. The crude was then purified by silica gel columnchromatography to give(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid propylamide (30 mg, 18.7% yield) as a white solid. MS calcd. forC₂₆H₃₆N₃O₃ [(M+H)⁺] 438.0, obsd. 438.2.

Example 13(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid isopropylamide

(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid isopropylamide was prepared from(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester and isopropylamine in an analogous manner to example12. MS calcd. for C₂₆H₃₆N₃O₃[(M+H)⁺] 438.0, obsd. 437.8.

Example 14(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid benzylamide

(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid benzylamide was prepared from(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester and benzylamine in an analogous manner to example 12.MS calcd. for C₃₀H₃₆N₃O₃ [(M+H)⁺] 486.0, obsd. 486.4.

Example 15 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide

Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amidewas prepared from(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester and pyrrolidine in an analogous manner to example 12.MS calcd. for C₂₇H₃₆N₃O₃ [(M+H)⁺] 450.0, obsd. 450.2.

Example 16(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid amide

To a solution of(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester (50 mg) in tetrahydrofuran (7 mL), aq. ammoniumhydroxide (15 mL) was added in a seal tube and the mixture was heatedfor 24 hrs at 95° C. The reaction mixture was concentrated and theaqueous layer was extracted with diethyl ether, washed with brine,dried, concentrated and was purified by column chromatography to obtain(2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid amide (8 mg, 16% yield) as a light brown solid. MS calcd. forC₂₃H₃₀N₃O₃ [(M+H)⁺] 396, obsd. 396.

Example 17(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester

(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4S)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylicacid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in ananalogous manner to example 1. MS calcd. for C₂₅H₃₃N₂O₄ [(M+H)⁺] 425,obsd. 425.

Example 18(2R,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester

(2R,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2R,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₄H₃₁N₂O₄[(M+H)⁺] 411, obsd. 411.

Example 19(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester

(2S,4R)-1-Cyclohexyltnethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4R)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₄H₃₁N₂O₄[(M+H)⁺] 411, obsd. 411.

Example 20(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid ethyl ester was prepared from(2S,4R)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylicacid methyl ester in an analogous manner to example 8. MS calcd. forC₂₅H₃₃N₂O₄[(M+H)⁺] 425, obsd. 425.

Example 21(2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylicacid methyl ester

(2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylicacid methyl ester was prepared from(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester and 1-amino-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₄H₃₂N₃O₃[(M+H)⁺] 410, obsd. 410.

Example 22(2S,4S)-1-Cyclohexylmethyl-4-[(8-hydroxy-quinoline-7-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester

(2S,4S)-1-Cyclohexylmethyl-4-[(8-hydroxy-quinoline-7-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester was prepared from(2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester and 8-hydroxy-quinoline-7-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₄H₃₂N₁O₄ [(M+H)⁺] 426, obsd. 426.

Example 23(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid methyl ester

(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid methyl ester was prepared from(2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₂₅H₃₃N₂O₄ [(M+H)⁺] 425, obsd. 425.

Example 24(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethyl ester

(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethyl ester was prepared from(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid methyl ester in an analogous manner to example 8. MS calcd. forC₂₆H₃₅N₂O₄ [(M+H)⁺] 439, obsd. 439.

Example 25(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethylamide

(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethyl ester was prepared from(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid methyl ester in an analogous manner to example 10. MS calcd. forC₂₆H₃₆N₃O₃ [(M+H)⁺] 438, obsd. 438.

Example 26 1-Hydroxy-naphthalene-2-carboxylic acid((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide

Step 1: Preparation of(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylicacid benzyl ester was prepared from(2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl esterand 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner toexample 1. MS calcd. for C₂₆H₂₄N₃O₅ [(M+H)⁺] 458, obsd. 458.

Step 2: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide

To a solution of(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylicacid benzyl ester (30 mg, 0.06 mmol) in methanol (2 mL) was added 20%Pd(OH)₂ (20 mg) and the mixture was stirred at room temp. for 16 h. witha balloon containing H₂ gas. The reaction mixture was then filtered andconcentrated under reduced pressure to give1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide (15 mg) as a light brownliquid. MS calcd. for C₁₈H₁₈N₃O₃[(M+H)⁺] 324, obsd. 324.

Step 3: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide

Hydroxy-naphthalene-2-carboxylic acid((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide wasprepared from 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide andcyclohexanecarbaldehyde in a similar fashion as the synthesis of(2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methylester. MS calcd. for C₂₅H₃₀N₃O₃[(M+H)⁺] 420, obsd. 419.8.

Example 27 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

Step 1: Preparation of(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester was prepared from(2S,4S)-4-amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogousmanner to example 1. MS calcd. for C₂₇H₂₆N₃O₅ [(M+H)⁺] 472, obsd. 472.

Step 2: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yI]-amide was preparedfrom(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester in an analogous manner to example 26. MS calcd. forC₁₉H₂₀N₃O₃ [(M+H)⁺] 338, obsd. 338.

Step 3: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

1-hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide was prepared from1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide in an analogousmanner to example 26. MS calcd. for C₂₆H₃₂N₃O₃ [(M+H)⁺] 434, obsd. 434.

Example 28 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

Step 1: Preparation of(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-ainino]-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonye-amino]-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester was prepared from(2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acidbenzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogousmanner to example 1. MS calcd. for C₃₂H₂₈N₃O₅ [(M+H)⁺] 534, obsd. 534.

Step 2: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide was preparedfrom(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester in an analogous manner to example 26. MS calcd. forC₂₄H₂₂N₃O₃ [(M+H)⁺] 400, obsd. 400.

Step 3: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide

1-Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amidewas prepared from 1-hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(5-phenyl-oxazol-2-yl)-pyiTolidin-3-yl]-amide in an analogousmanner to example 26. MS calcd. for C₃₁H₃₄N₃O₃ [(M+H)⁺] 496, obsd. 496.

EXAMPLE 29 1-Hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

Step 1: Preparation of(2S,4S)-2-benzooxazol-2-yl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-1-carboxylicacid benzyl ester

(2S,4S)-2-benzooxazol-2-yl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-1-carboxylicacid benzyl ester was prepared from(2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzylester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous mannerto example 1. MS calcd. for C₃₀H₂₆N₃O₅[(M+H)⁺] 508, obsd. 508.

Step 2: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-pyrrolidin-3-yl)-amide

1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-pyrrolidin-3 -yl)-amide was prepared from(2S,4S)-2-benzooxazol-2-yl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-1-carboxylicacid benzyl ester in an analogous manner to example 26. MS calcd. forC₂₂H₂₀N₃O₃ [(M+H)⁺] 374, obsd. 374.

Step 3: Preparation of 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amidewas prepared from 1-hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-pyrrolidin-3-yl)-amide in an analogousmanner to example 26. MS calcd. for C₂₉H₃₂N₃O₃[(M+H)⁺] 470, obsd. 470.

BIOLOGICAL EXAMPLES

Determination of compounds HCV GT1b inhibitory replicon activity usingthe replicon luciferase reporter assay

The 2209-23 cell line was developed at Roche by stable transfection ofthe hepatoma cell line Huh-7 with a GT-1b Con1 subgenomic bicistronicreplicon as previously described. Subgenomic replicon cell line wasestablished in cured Huh7 cells, obtained from R. Bartenschlager (JVirol. 2003 March; 77 (5):3007-19) The GT-1a H77 subgenomic repliconvector pRLuc H77 1b 75 S/I, was created by replacing the nonstructuralregion of the GT-1b Con1 subgenomic replicon by the one of the H77strain, except for the first 75 amino acids of the NS3 protein that arefrom GT-1b Conl strain. (J. Virol. 2001 77:5352-59) The GT-1a pRLuc H771b 75 S/I subgenomic replicon cell line was established in cured Huh7cells, obtained from R. Bartenschlager. (J Virol. 2003 March; 77(5):3007-19)

All the subgenomic replicon cell lines were cultured in Dulbecco'sModified Eagle Medium (DMEM-Glutamax™-I; Invitrogen Cat #10569-010). Themedium was supplemented with 10% Fetal Bovine Serum (Invitrogen Cat#10082-147), 1% penicillin/streptomycin (Mediatech Cat #30-002-CI) and500 μg/ml of G418 (Mediatech Cat #30-234-CI). Cells were maintained at37° C. in a humidified 5% CO₂ atmosphere.

2209-23 cells were plated at a cell density of 5000 cells per well in 96well plates (Becton Dickinson, Cat #35 3296). Cells were plated in 90 μlof Dulbecco's Modified Eagle Medium (DMEM-Glutamax™-I), (Invitrogen Cat#10569-010) medium was supplemented with 5% Fetal Bovine Serum(Invitrogen Cat #10082-147), 1% penicillin/streptomycin (Mediatech Cat#30-002-CI). The pRluc H77 1b 75 SA cells were plated in 96-well plateat 3000 cells/well in DMEM-Glutamax™-I containing 5% FBS and 1%penicillin/streptomycin in 90 μl final volume. Cells were allowed toequilibrate for 24 hours at 37° C. and 5% CO2 at which time compoundswere added. Compounds (or medium as a control) were added 24 hourspost-plating in 3 fold dilutions at a final DMSO concentration of 1% in10 μl volume. Renilla luciferase reporter signal was read 72 hours afteraddition of compounds using the Renilla Luciferase Assay System(Promega, cat #E2820). EC50 values were defined as the compoundconcentration at which a 50% reduction in the levels of renillaluciferase reporter was observed as compared to control samples in theabsence of compound and was determined by non-linear fitting of compounddose-response data. The EC50 was approximated if maximum percentageinhibition was less than 90% and more than 70%.

Determination of compounds cytotoxicity using the HCV GT1b replicon cellline measuring WST1. 2209-23 cells were plated at a cell density of 5000cells per well in clear flat-bottom 96 well plate (Becton Dickinson, Cat#35 3075) for cell viability studies. The WST-1 cell proliferation assay(Roche Diagnostic, Cat #11644807001) was used to determine cellviability. Assay plates were set up in the same format as in thereplicon assay. After 3 days of compound incubation 10 μl of WST-1reagent was added to each well for 2 hours at 37° C. and 5% CO₂,following manufacturer's instructions. Absorption reading at 450 nm(reference filter at 650 nm) was determined using MRX Revelationmicrotiter plate reader (Lab System). CC₅₀ values were defined as thecompound concentration required for reducing cell viability by 50% ascompared to the untreated control in absence of compound and wasdetermined by non-linear fitting of compound dose-response data.Representative assay data can be found in Table II below:

TABLE II Compound # GT-1a - EC₅₀ (nM) # HCV, GT1b, IC₅₀ (□M) I-1 0.047I-2 0.079 I-3 0.051 I-4 0.029 I-5 0.052 I-6 0.055 I-7 0.070 I-8 0.086I-9 0.114 I-10 0.120 I-11 0.121 I-12 0.129 I-13 0.163 I-14 0.184 I-150.187 I-16 0.205 I-17 0.219 I-18 0.221 I-19 0.223 I-20 0.233 I-21 0.247I-22 0.299 I-23 0.336 I-24 0.367 I-25 0.509 I-26 0.64 I-27 0.659 I-280.793 I-29 0.826

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1. A compound of Formula

wherein: A is CH or N; n is 1 or 2; R¹ is lower alkyl, cycloalkyl,phenyl, or heterocycloalkyl; R² is —C(═O)OR^(2′), —C(═O)N(R^(2′))₂,monocyclic or bicyclic heteroaryl, optionally substituted with one ormore R^(2′); each R^(2′) is independently H, lower alkyl orheterocycloalkyl; R³ is H or lower alkyl; R⁴ is hydroxyl or amino; and Xis CH₂ or C(═O); or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 2, wherein R³ is H and X is CH₂.
 3. The compound ofclaim 2, wherein n is
 2. 4. The compound of claim 2, wherein n is
 1. 5.The compound of claim 4, wherein R² is —C(═O)N(R^(2′))₂,
 6. The compoundof claim 4, wherein R² is monocyclic or bicyclic heteroaryl, optionallysubstituted with one or more R^(2′).
 7. The compound of claim 4, whereinR² is —C(═O)OR^(2′).
 8. The compound of claim 7, wherein R^(2′) is loweralkyl.
 9. The compound of claim 8, wherein R¹ is lower alkyl orcycloalkyl.
 10. The compound of claim 9, wherein R¹ is cyclohexyl.
 11. Acompound selected from the group consisting of: (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid tent-butyl ester;(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester;(2S,4R)-1-Cyclohexyhnethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester; 1-Hydroxy-naphthalene-2-carboxylic acid((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid methyl ester; 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester;(2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester;(2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid benzylamide;(2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid isopropylamide; (2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acidpropylamide;(2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-prrolidine-2-carboxylicacid ethylamide;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylicacid ethylamide;(2R,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylicacid methyl ester;(2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylicacid methyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(8-hydroxy-quinoline-7-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid amide; 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide;(2S,4R)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid ethyl ester;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylicacid methyl ester; and 1-Hydroxy-naphthalene-2-carboxylic acid[(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amide.12. A compound according to any one of claims 1 to 11 for use astherapeutically active substance.
 13. The use of a compound according toany one of claims 1 to 11 for the treatment or prophylaxis of aHepatitis C Virus (HCV) infection.
 14. The use of a compound accordingto any one of claims 1 to 11 for the preparation of a medicament for thetreatment or prophylaxis of a Hepatitis C Virus (HCV) infection.
 15. Acompound according to any one of claims 1 to 11 for the treatment orprophylaxis of a Hepatitis C Virus (HCV) infection.
 16. A method fortreating a Hepatitis C Virus (HCV) infection comprising administering toa patient in need thereof a therapeutically effective amount of acompound of any one of claims 1-11.
 17. A pharmaceutical compositioncomprising a compound of any one of claims 1-11 and a pharmaceuticallyacceptable excipient.
 18. The invention as hereinbefore described.